Decoding the Metabolic Secrets of MAIT Cells: Sugar versus Fat

A new study conducted by researchers at the La Jolla Institute for Immunology (LJI) has unveiled intriguing insights into mucosal-associated invariant T (MAIT) cells. These unique white blood cells, located primarily in tissues rather than circulating in the bloodstream, play a crucial role in defending against a wide range of diseases. By unraveling the mysteries of MAIT cell biology, the study offers potential pathways for the development of innovative vaccines and cell therapies that can bolster the immune system’s ability to combat specific pathogens.

Led by LJI scientists Mitchell Kronenberg, Ph.D., and Thomas Riffelmacher, Ph.D., the research delved into the location, function, gene expression, and metabolism of MAIT cells in mouse lungs. It sought to explore how the metabolic programming of these cells can be adjusted to effectively target diverse pathogens, opening new avenues for therapeutic interventions.

Metabolism, as Dr. Riffelmacher explains, refers to how cells utilize fuel molecules to carry out their tasks. Recent breakthroughs in the field have linked T cell function to their metabolic programming, but until now, this relationship had not been investigated in MAIT cells.

The study discovered two distinct categories of MAIT cells, each with its unique characteristics. One subtype, fueled by sugar, is specialized in combating viral infections, while the other, fueled by fat, is geared towards fighting bacterial infections. These findings hold promise for inspiring the development of novel vaccines and cell therapies that can modulate the balance between these two cell groups, enhancing the individual’s ability to combat specific pathogens.

The investigation further revealed that MAIT cells exhibit memory-like responses following infections, resulting in increased cell numbers and more robust protective responses that persist long after the pathogen has been eliminated from the body. Driven by a desire to understand the molecular changes underlying this essential memory function, Dr. Riffelmacher introduced a live bacterial vaccine strain to a mouse model. The result was a hundredfold expansion of MAIT cells in the lungs, unexpectedly giving rise to two distinct subsets of cells within the expanded population.

Characterizing these two lineages through a series of comprehensive experiments unveiled several unique properties. One subset, known as MAIT1 cells, predominantly located along blood vessels in the lung, launched a type 1 immune response marked by the secretion of interferon-gamma (IFN-γ). These cells specialized in combatting intracellular microbes, such as influenza viruses. The other subset, called MAIT17 cells, primarily found in lung tissue, initiated a type 17 immune response characterized by the secretion of interleukin-17 (IL-17). MAIT17 cells focused on combating extracellular microbes, including bacteria like those responsible for pneumonia, such as Streptococcus pneumoniae.

Additionally, the researchers purified MAIT1 and MAIT17 cells and transferred them into new mice, observing that both populations enhanced the animals’ immunity compared to untreated mice. However, MAIT1 cells offered superior protection against the influenza virus, while MAIT17 cells demonstrated efficacy against Streptococcus pneumoniae, the most common cause of pneumonia.

Notably, the metabolic programs of these two cell types diverged significantly. Each subtype relied on a distinct energy source for sustenance. MAIT1 cells, in a low-energy dormant state until activation, utilized sugar (glycolysis) as their primary fuel. In contrast, highly active MAIT17 cells required a constant supply of fatty acids to generate energy through their mitochondria. Confirming the influence of metabolism on MAIT cell responses, the researchers genetically manipulated white blood cell metabolism to favor glycolysis, resulting in elevated numbers of MAIT1 cells.

While the study’s findings shed light on the metabolic disparities between MAIT cell subsets, it’s important to note that dietary habits cannot directly influence MAIT cell function. Although diet can impact metabolite distribution in the body, cellular and organismal metabolism operate differently. Therefore, there is no evidence to support the notion that altering eating patterns would affect MAIT cell function.

However, the researchers propose that by pharmacologically modulating the levels of specific metabolites, it may be possible to shift the MAIT cell response in humans to improve their ability to combat viral infections or bacteria. This could involve developing vaccines that activate either MAIT1 or MAIT17 cells or transplanting one cell subtype into patients to enhance a particular immune response. The conservation of MAIT cells and their key signaling protein across individuals and species suggests that they are less likely to trigger a graft-versus-host response, making them a potentially valuable tool for immunotherapy.

Dr. Kronenberg envisions a future where selective enhancement of MAIT1 or MAIT17 cells is possible, enabling patients to tune their immune systems to effectively combat different pathogens as needed.

The study, funded by the National Institutes of Health and the Wellcome Trust, was published in Nature Cell Biology.

Reference: Riffelmacher, T., Murray, M. P., Wientjens, C., Chandra, S., Cedillo-Castelán, V., Chou, T.-F., McArdle, S., Dillingham, C., Devereaux, J., Nilsen, A., Brunel, S., Lewinsohn, D. M., Hasty, J., Seumois, G., Benedict, C. A., Vijayanand, P., & Kronenberg, M. (2023). Divergent metabolic programmes control two populations of MAIT cells that protect the lung. Nature Cell Biology, 1–13. https://doi.org/10.1038/s41556-023-01152-6

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More about MAIT cells

• La Jolla Institute for Immunology (LJI): Website
• Nature Cell Biology: Research Article
• National Institutes of Health (NIH): Website
• Wellcome Trust: Website